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Objectives

The following module was designed following the objectives of the Canadian Oncology Goals and Objectives for Medical Students for esophageal cancer. Information on epidemiology, risk factors, prevention, screening, presentation, diagnosis, and prognosis for esophageal cancer is provided.

By the end of the tutorial, the following objectives should be addressed:

  1. Understand basic anatomy of esophagus and nearby lymph nodes and structures
  2. Identify common risk factors associated with esophageal cancers
  3. Discuss the importance of genetics as a risk factor for esophageal cancer
  4. Describe the common signs and symptoms of esophageal cancer
  5. Understand the classification and staging of esophageal cancers
  6. Understand Barrett’s Esophagus and its relation to esophageal cancer
  7. Understand general approach to esophageal cancer diagnosis
  8. Understand the laboratory tests, imaging techniques, and biopsy methods used in the investigation of esophageal cancer
  9. Describe neoadjuvant, adjuvant, and definitive management options for esophageal cancer

Extra detailed content will be provided in certain sections under an expandable and collapsible header for interest reading or for higher level learners. The content will expand on each section or provide insight into new objectives not covered under the Canadian oncology objectives for medical students.

Anatomy

Esophageal Anatomy
Gray, Henry. (1918). Anatomy of the Human Body (20th edition). Philadelphia and New York.

The esophagus is a 25cm distensible tube which connects the pharynx and the stomach. Its superior border is the hypopharynx (C6 vertebra), passess through the posterior mediastinum, enters the abdomen at the esophageal hiatus of the diaphragm, and terminates at the esophagogastric junction (EGJ). The esophagus can be divided into 3 anatomic parts: cervical, thoracic, and abdominal esophagus.

The blood supply of the cervical esophagus is derived from the inferior thyroid artery, while the blood supply for the thoracic esophagus is derived from the bronchial arteries and the aorta. The abdominal esophagus is supplied by branches of the left gastric artery and inferior phrenic artery.

The esophagus is characterized by a rich network of lymphatic channels in the submucosa that can facilitate longitudinal spread of neoplastic cells along the esophageal wall. Lymphatic drainage is to the cervical, traceobronchial, mediastinal, gastric, and celiac node basins.


Histology

The wall of the esophagus is divided into four main layers. From inside to outside, these are:

  1. Mucosa 
  2. Submucosa
  3. Muscularis propria
  4. Adventitia

Detailed sections of the esophagus

  • Cervical esophagus: runs posterior to the trachea for 4-5cm before ending at the level of the thoracic inlet. This segment borders the carotid sheath, recurrent laryngeal nerve, and thyroid gland bilateralyl as well as teh thoracic duct to the left. Posteriorly, the cervical esophagus rests on the vertebral column.
  • Thoracic esophagus: spans from the thoracic inlet to the EGJ at the level of T11. This segment is subdivided into the upper thoracic, midthoracic, and lower thoracic regions. The border between the upper and mid-thoracic esophagus is at the level of the tracheal bifurcation. The mid-thoracic esophagus continues to the level of the inferior pulmonary veins, where it becomes the lower thoracic esophagus.
  • Abdominal esophagus: a short segment of the esophagus below the esophageal hiatus which overlaps with the lower thoracic esophagus. The abdominal esophagus is primarily retroperitoneal, although a small portion is covered by peritoneum/serosa. Inside the abdomen, the esophagus passes behind the left lobe of the liver.

Lymph nodes: For lymph node stations for staging and management of esophageal cancer, refer to this publication by Wang et al. 2018 detailing the anatomy of the lymph nodes: https://doi.org/10.2147/CMAR.S182436 [1].

Histological layers of the esophagus

  • Mucosa: consists of stratified squamous epithelium, lamina propria, and muscularis mucosa. The squamocolumnar junction (Z-line) separates the stratified squamous epithelium of the esophagus and simple columnar epithelium of the stomach. Normally the Z-line coincides with the EGJ, however, in Barrett’s esophagus, metaplasia causes the squamocolumnar junction to migrate proximally.
  • Submucosa:
  • Muscularis propria: the upper third of the esophagus is striated muscle while the lower third is smooth muscle. A mixture of both striated and smooth muscle can be found in the middle third of the esophagus.
  • Adventitia: thin and with small amount of peritoneal (serosal) covering of the abdominal esophagus. The esophagus’s thin adventitia and lack of serosa facilitate the locoregional progression of esophageal cancer.

Classification

Esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC) account for >95% of esophageal malignant tumors. For most of the twentieth century, squamous cell carcinoma comprised the vast majority of esophageal cancers, however, in the last two decades, the incidence of adenocarcinoma of the esophagus has increased dramatically. The predominance of adenocarcinoma is observed in high-income Western countries including the US [2].


Squamous Cell Carcinoma

ESCC is characterized by extensive local growth and lymph node metastasis. Direct invasion of adjacent struea, carotid arteries, vagus nerve, bronchus, aorta, and pericardium) occur early. ESCC has a predilection for the middle third of the esophagus. Esophageal cancer involving the upper third of the esophagus is rare but predominantly ESCC when it occurs. [3]

Adenocarcinoma

EAC of the esophagus tend to be less locally invasive and have more rapid spread to lymph nodes. The spread of adenocarcinoma is not as ordered as SCC and tend to metastasis widely to different areas. It has a predilection to arise from the lower third of the esophagus.

Other

Much rare cancers involving the esophagus include adenocystic, mucoepidermoid, small cell, and sarcomatoid carcinomas as well as lymphoma, Kaposi sarcoma, and melanoma; individually, these account for less than 1% of esophageal cancers [4].

Adenocarcinoma near the cardia are further grouped by the Siewert classification which has implications for treatment.

  • Type I: tumor epicenter location 1-5cm above the EGJ.
  • Type II: tumor epicenter located 1cm above to 2cm below the EGJ. These are the true tumors of the cardia.
  • Type III: tumor epicentre located 2-5cm below the EGJ.

Siewert type I and II adenocarcinomas are stages as esophageal cancer while Siewert type III adenocarcinomas are staged as gastric cancers [6].

Epidemiology

One in 250 females and one in 98 males are expected to develop esophageal cancer during their lifetime. In BC, the incidence rates of esophageal cancers diagnosed is 9.6 males per 100,000, and 3.7 females per 100,000 per year. It was responsible for 2,200 deaths in Canada in 2017 owing to the advanced stage at which most are diagnosed [6]. It is less common in the West compared to globally where is ranks 9th in incidence and 6th in mortality among cancers [7].


Many esophageal cancer risks depend on the subtype of cancer, for example esophageal adenocarcinoma (EAC) vs. esophageal squamous cell carcinoma (ESCC). There is a trend toward higher incidence rates of EAC and lower incidence rates of ESCC in high-income Western countries and this can be attributed to increasing rates of obesity and GERD, which are strongly associated with EAC, and decreasing rates of smoking, a leading cause of ESCC [9, 10]. 


In general, esophageal cancer affects men 3-4 times more than women. African-americans are twice as likely to develop esophageal cancer than caucasian people. Smoking, alcohol-intake, obesity, and lower esophageal irritation (GERD, Barrett’s esophagus) are major risk factors for esophageal cancers overall.

Summary of risk factors

A summary of risk factors for ESCC and EAC is below in Table 1. Esophageal cancer is relatively rare, so the risk of developing esophageal cancer in most patients with these risk factors remains low. The next section will cover prevention and screening. Please see the expandable section below for details and evidence regarding specific risk factors.

Table 1. Summary of esophageal cancer risk factors

Histology Risk factors
General or unspecified

Male
Higher age
Heat and caustic injury
Radiation therapy exposure

Esophageal adenocarcinoma (EAC) Elevated BMI
Symptoms of GERD
Barrett's esophagus
Tobacco smoking
Diets rich in meat
Diets lacking fruits and vegetables
Caucasian race
Achalasia
Esophageal squamous cell carcinoma Tobacco smoking
Alcohol consumption
Achalasia
Heat and caustic injury
Hereditary conditions: Plummer-Vinson syndrome, Fanconi anemia, Bloom syndrome, tylosis
Personal history of head and neck SCC
HPV infection and nutritional deficiences, but less relevant in Western populations

 

We will cover in more detail the specific risk factors for esophageal cancer as outlined in Table 1.

  • Tobacco smoking: there is a strong relationship between smoking and the risk of developing ESCC and EAC [11]. Tobacco and alcohol consumption appear to have a synergistic effect on the risk of ESCC [12].

  • Alcohol: heavy alcohol consumption has been found to increase the risk of developing ESCC but not EAC [13]. Alcohol and tobacco smoking synergistically increase the risk of ESCC [12].

  • Obesity: overweight and obese patients are at increase risk of developing EAC, possibly as a result of increased GERD [14]. In contrast, elevated BMI appears to have a protective effect in ESCC [15].

  • GERD: patients with GERD are at a markedly higher risk of developing EAC. Prolonged, more frequent, and more severe reflux symptoms confers additional risk [16].

  • Barrett's esophagus: Barrett’s esophagus has a 1-7% general population prevalence and 5-15% in patients with GERD. It is believed to be a precursor to most cases of EAC [17], and patients with Barrett’s esophagus are estimated to have a 0.5% annual risk of developing EAC.

  • Diet: diets rich in meat, particularly red, increase the risk of EAC. Alternatively, fruits and vegetable consumption may have a protective role in EAC [18]. There is evidence that nutritional deficiences in riboflavin, nicotinic acid, magnesium, and zinc account for increased risk of ESCC observed in high-risk regions [19].

  • Achalasia: achalasia dramatically increases the risk of ESCC and, to a lesser extent, EAC [20]. It is worth noting that obstruction by lower esophageal cancer can resemble achalasia, leading to misdiagnosis. As a result, the risk of esophageal cancer is especially high in the first year following the diagnosis of achalasia.

  • Sex: when adjusting for age, men are around 4x more likely to develop esophageal cancer [21].

  • Age: the incidence rate of esophageal cancer increases with age. Among those newly diagnosed with esophageal cancer in the US, 98% are at least 45 years old [22].

  • Race and Ethnicity: geographically, the incidence of esophageal cancer is highest in East Asia, followed by Southern Africa, Eastern Africa, and Northern Europe [8]. While most esophageal cancers diagnosed in these high-incidence regions at ESCC, their etiology is less clear than those diagnosed in the West [8]. Possible culprits include HPV infection and dietary deficiencies, but a causal link has not been established [23].

    In the US, Caucasians have higher incidence rates of esophageal cancer than Asians, Hispanics, American Indians, and Blacks. Caucasians are at particular risk for EAC, while Blacks and Asians more commonly develop ESCC [22].

Preventing & Screening

Prevention

Prevention includes primarily the avoidance of environmental triggers including quitting smoking or avoiding exposure to tobacco and cigarette smoke. Avoid excessive alcohol use with complete avoiding reducing your cancer risk the most. The American Institute for Cancer Research advises less than two drinks a day for men and one per day for women. Healthy eating and regular physical exercise to maintain a healthy BMI can lower risk for esophageal cancer.

For patients with Barrett’s Esophagus, it is recommended that they receive appropriate treatment and follow their surveillance schedule (see below).

Screening

Currently no effective screening program exists for esophageal cancer in any Western organization. There is, however, interest in screening patients with reflux which has been described by the American College of Physicians, the American College of Gastroenterology, and the American Society of Gastrointestinal Endoscopy [25-27]. 

Guidelines agree that upper endoscopy is indicated in patients presenting with GERD and concomitant warning symptoms described below [25-27]. The ACP and ASGE recommend investigating reflux symptoms that are refractory to treatment. Endoscopy may also be appropriate in patients with longstanding or severe reflux symptoms and multiple additional risk factors including:

  • 1. Male sex
  • 2. Age >50
  • 3. Caucasian race
  • 4. Elevated BMI
  • 5. Known hiatal hernia
  • 6. History of tobacco smoking
  • 7. Nocturnal reflux symptoms
  • 8. Positive first-degree family history of EAC or Barrett's esophagus.

Patients who do not have any evidence of EAC or Barrett’s esophagus on screening endoscopy do not need repeat endoscopy. On the other hand, patients found to have Barrett’s esophagus should consider endoscopic surveillance and treatment of dysplasia. People with known Barrett’s esophagus have specific screening recommendations (see below).

Severe caustic injury is associated with ESCC, allegedly increasing risk by a thousandfold. There is, on average, a 40-year latency between the time of injury and the development of esophageal cancer. The ASGE recommends beginning endoscopic surveillance 15-20 years after injury [28].

Achalasia increases the risk of developing esophageal cancer (1 in 300 patient-years). However, the number of endoscopies needed for each early diagnosis (400) and poor prognosis in this patient group has led the ACG and ASGE to withhold their endorsement, and practice within the field varies [48].

Hereditary cancer syndromes can be considered case-by-case for screening owing to their heterogeneity. The NCCN provides screening recommendations for some genetic conditions implicated in esophageal cancer: https://www.nccn.org/professionals/physician_gls/pdf/esophageal.pdf.

Barrett’s Esophagus

Inflammation of esophagus is called esophagitis. There are many causes of esophagitis; in North America, the most common cause is regurgitation of gastric contents through the lower esophageal sphincter (Gastro-Esophageal Reflux Disease (GERD)). The acid gastric contents irritate the esophagus squamous mucosa causing inflammation. In some individuals, persistent reflux may cause squamous mucosa to undergo metaplastic transformation into glandular epithelium which is then called Barrett’s esophagus. The risk of progression to adenocarcinoma of the esophagus depends on factors including the length of Barrett’s (short vs. long segment), and the grade of dysplasia (low vs. high-grade dysplasia).

Table 2. Grade of Barrett's Esophagus and recommended surveillance and treatment

Grade of Dysplasia Endoscopic & Surveillance recommendations
No dysplasia Endoscopic treatment not recommended, surveillance endoscopy every 3 - 5 years
Low-grade dysplasia Endoscopic treatment can be considered, and in its absence, surveillance endoscopy every 6 - 12 months
High-grade dysplasia Endoscopic ablation/esophagectomy recommended, and in its absence, surveillance endoscopy every 3 months

 

Presentation & Diagnosis

Symptoms depend on location of tumor. Early esophageal cancer is usually asymptomatic. Overall, dysphagia and weight loss are the most common symptoms at time of diagnosis, presenting in 74% and 57% of patients respectively [24].  Other rarer (present in <20%) symptoms include odynophagia, symptoms of reflux refractory to treatment, recurrent vomiting, evidence of upper GI bleed, dyspnea, hoarseness due to recurrent laryngeal nerve involvement, and cervical lymphadenopathy [24]. Physical examination is usually normal in patients with esophageal cancer, and positive findings such as a palpable mass, lymphadenopathy, organomegaly, or cardiorespiratory abnormalities imply very advanced disease. 

Diagnosis

Diagnosis should begin with a detailed history and physical examination. Esophageal cancer specific history questions and physical exam findings are detailed below.

History

Physical

Inquire about warning symptoms associated with esophageal cancer:

  1. (Progressive) dysphagia
  2. Unexplained weight loss
  3. Odynophagia
  4. Early satiety
  5. Evidence of GI obstruction
  6. Persistent vomiting
  7. Hematemesis
  8. Hemoptysis
  9. Melena
  10. Iron deficiency anemia
  11. Dyspnea
  12. Hoarseness
  13. Chest pain

Review of systems
Smoking history
Alcohol consumption
Diet
Past medical history with emphasis on GERD, previous malignancies and its treatment, previous injury or surgery
Family history

Vital signs, weight, and height.

Head and Neck Exam:

  1. Masses
  2. Cervical lymphadenopathy
  3. Consider nasopharyngolaryngoscopy

Cardiorespiratory exam:

  1. Decreased breath sounds, hyporesonance
  2. Pleural effusion
  3. Cardiac dysfunction

Abdominal exam:

  1. Abdominal distension, masses, or lymphadenopathy
  2. Hepatomegaly, jaundice
  3. Supraclavicular lymph nodes
  4. Axillary lymph nodes
  5. Consider DRE

Consider other findings associated with common sites of metastases — liver, lung, and bone.

In the absence of an alternative explanation, patients experiencing any of the warning symptoms described in Table 2 require further investigation [30, 31]. Upper endoscopic examination with biopsy is the diagnostic test of choice for esophageal cancer. In addition to cancer, upper endoscopy is also valuable in ruling out many other causes of these warning symptoms. The value of routinely adding barium swallow to endoscopy, as is traditional, is unclear; however, barium swallow is compulsory if there is a suspicion for tracheoesophageal fistula [31].

Post-diagnostic workup

Investigations

Comments

1. Laboratory investigations

CBC, extended electrolytes, urea, creatinine, liver function tests, alkaline phosphatase.
Consider tumor markers such as CEA and CA 19-9.

2. Endoscopic ultrasound (unless metastatic or known unresectable)

Assess tumor depth and perform fine needle aspiration of any suspicious nodes. For T and N staging.

3. Endoscopic resection of cT1a and small (up to 2cm) cT1b tumors

For staging and potentially curative treatment.

4. Bronchoscopy if tumor located at or above the level of the carina

To rule out any airway invasion.

5. Consider thoracoscopy, mediastinoscopy, or laparoscopy ± cytology for surgical candidates

To rule out advanced disease that may affect operative approach or possibly preclude operative management.

6. PET/CT skull base to mid-thigh if no evidence of metastatic disease

Staging investigation.

7. Consider CT or MRI chest and abdomen

To investigate specific symptoms or for surgical planning (examine tissue planes and vessel involvement).

8. Consider PFTs

Helpful for radiotherapy or surgical candidates, especially if there is uncertainty about pulmonary reserves.

9. HER2-neu status for M1 adenocarcinoma

To assess for trastuzumab candidacy.

10. Consider MSI-H/dMMR and PD-L1 status for M1 disease with availability of pembrolizumab for esophageal cancer.

Pembrolizumab has received fast-track approval by the FDA; it is not widely available in Canada.

Staging and Grading

TX: primary tumor cannot be assessed
T0: no evidence of primary tumor
Tis: high-grade or dysplasia
T1a: tumor invades lamina propria or muscularis mucosa
T1b: tumor invades submucosa
T2: tumor invades muscularis propria
T3a: tumor penetrates adventitia
T4a: tumor invades pleura, pericardium, azygos vein, or peritoneum
T4b: tumor invades other adjacent structures such as the aorta, an airway, or a vertebral body

NX: lymph nodes cannot be assessed
N0: no regional lymph node metastases
N1: 1-2 positive regional lymph nodes
N2: 3-6 positive regional lymph nodes
N3: 7 or more positive regional lymph nodes
*regional lymph nodes refer to lower cervical paratracheal; upper and lower paratracheal; subcarinal; upper, middle, and lower thoracic esophageal; pulmonary ligament; diaphragmatic, paradarcial; left gastric; common hepatic; splenic; celiac; and cervical periesophageal H&N level VI and VII nodes

M0: no distant metastases
M1: distant metastases are present

GX: grade not available
G1: well differentiated
G2: moderately differentiated
G3: poorly differentiated

Whether the tumor is located in the upper (cervical and upper thoracic), middle (midthoracic), or lower (lower thoracic) esophagus affects staging in some cases. The 8th edition of the AJCC Cancer Staging Manual defines tumor location based on its epicenter as opposed to its proximal border, a departure from previous editions.

Clinical (cTNM)

Stage 0: Tis N0 M0
Stage I: T1 N0-1 M0
Stage II: T2 N0-1 M0 or T3 N0 M0
Stage III: T3 N1 M0 or T1-3 N2 M0
Stage IVA: T4 N0-3 M0 or T1-4b N3 M0
Stage VB: M1

Post-neoadjuvant therapy (ypTNM)

Stage I: T0-2 N0 M0
Stage II: T3 N0 M0
Stage IIIA: T0-2 N1 M0
Stage IIIB: T3 N1 M0 or T0-3 N2 M0 or T4a N0 M0
Stage IVA: T4a N1-2 M0 or T4b M0 or N3 M0
Stage IVB: M1

Pathologic (pTNM)

Stage 0: Tis N0 M0
Stage IA: T1a N0 M0 G1/X
Stage IB: T1a N0 M0 G2-3 or T1b N0 M0 G1-3/X or T2 N0 M0 G1
Stage IIA: T2 N0 M0 G2-3/X or T3 N0 M0 G1-3 lower or T3 N0 M0 G1 upper/middle
Stage IIB: T3 N0 M0 G2-3 upper/middle or T3 N0 M0 GX or T1 N1 M0 G1-3/X
Stage IIIA: T1 N2 M0 G1-3/X or T2 N1 M0 G1-3/X
Stage IIIB: T2-3 N2 M0 G1-3/X or T3 N1 M0 G1-3/X or T4a N0-1 M0 G1-3/X
Stage IVA: T4a N2-3 M0 G1-3/X or T4b N0-3 M0 G1-3/X or T1-4b N3 M0 G1-3/X
Stage IVB: M1 disease

Whether the tumor is located in the upper (cervical and upper thoracic), middle (midthoracic), or lower (lower thoracic) esophagus affects staging in some cases. The 8th edition of the AJCC Cancer Staging Manual defines tumor location based on its epicenter as opposed to its proximal border, a departure from previous editions.

Clinical (cTNM)

Stage 0: Tis N0 M0
Stage I: T1 N0 M0
Stage IIA: T1 N1 M0
Stage IIB: T2 N0 M0
Stage III: T2 N1 M0 or T3-4a N0-1 M0
Stage IVA: T4b N0-3 M0 or T1-4 N2-3 M0
Stage IVB: M1

Post-neoadjuvant therapy (ypTNM)

Stage I: T0-2 N0 M0
Stage II: T3 N0 M0
Stage IIIA: T0-2 N1 M0
Stage IIIB: T3 N1 M0 or T0-3 N2 M0 or T4a N0 M0
Stage IVA: T4a N1-2 M0 or T4b N0-3 M0 or T1-4b N3 M0
Stage IVB: M1

Pathologic (pTNM)

Stage 0: Tis N0 M0
Stage IA: T1a N0 M0 G1/X
Stage IB: T1a N0 M0 G2 or T1b N0 M0 G1-2/X
Stage IC: T1a-b N0 M0 G3 or T2 N0 M0 G1-2
Stage IIA: T2 N0 M0 G3/X
Stage IIB: T1 N1 M0 G1-3/X or T3 N0 M0 G1-3/X
Stage IIIA: T1 N2 M0 G1-3/X or T2 N1 M0 G1-3/X
Stage IIIB: T2 N2 M0 G1-3/X or T3 N1-2 M0 G1-3/X or T4a N0-1 M0 G1-3/X
Stage IVA: T4a N2 M0 G1-3/X or T4b N0-3 M0 G1-3/X or T1-4b N3 M0 G1-3/X
Stage IVB: M1 disease.

Management

Management options for esophageal cancer depend on stage, patient preferences, patient factors and general health, and local expertise and practice. Surgery, radiotherapy, and systemic therapy all have well-established roles in the management of esophageal cancer. Treatment plans usually benefit from multidisciplinary consultation and discussion. 

An overview of the management of esophageal cancer is provided below. 

Features

Treatment

Tis or T1a

Endoscopic therapy is preferred for most cases.
Patients with more extensive disease may benefit from esophagectomy ± postoperative chemoradiotherapy or chemotherapy for positive margins or pN+.

Surgical candidate with low-risk T1b-2N0

Select patients with superficial T1b adenocarcinoma may be candidates for endoscopic therapy.
Otherwise esophagectomy ± postoperative chemoradiotherapy or chemotherapy for positive margins or pN+.
Consider treating higher-risk (>2cm or G2-3) tumors as more advanced disease.

Surgical candidate with T3-4a or N+

Options:

  1. Surgery with preoperative chemoradiotherapy (preferred)
  2. Definitive chemoradiiotherapy and assess response
  3. Adenocarcinoma only: Surgery with preoperative or perioperative chemotherapy

For unresectable disease, try chemoradiotherapy or systemic therapy before reassessing candidacy for resection.

Surgical candidate with T4b

Definitive chemoradiotherapy and assess response, may consider esophagectomy with downstaging
Omitting radiotherapy may be more appropriate if there is involvement of the trachea, heart, or great vessels.

Non-surgical candidate (including most cases of cervical esophageal cancer)

Tis, T1a, T1bN0: endoscopic therapy ± postoperative chemoradiotherapy for higher-risk T1b disease.
More advanced locoregional disease: definitive chemoradiotherapy if tolerated, if not provide palliative RT or supportive care.

Metastatic disease

Consider systemic, including targeted, therapy for patients with good performance status.
Palliative/supportive care otherwise.

Locoregional Disease

Endoscopic therapy

Endoscopic resection, by either endoscopic mucosal resection or endoscopic submucosal dissection, is the treatment of choice for small (up to 2cm) Tis, T1a, or superficial T1b disease without evidence of nodal metastases, lymphovascular invasion, or grade 3 histology (poor differentiation). Ablation after endoscopic resection can be considered, especially for T1b tumors [33]. These early-stage tumors are rarely associated with nodal metastases, so lymph node dissection may be omitted [32]. Patients with Tis or T1a disease who receive endoscopic resection appear to have similar overall survival outcomes as those who undergo esophagectomy, at considerably less morbidity [34-36]. Endoscopic resection is also appropriate in T1b patients who are unfit for surgery [33]. While the risk of lymph node metastases is substantially higher in this population, outcomes might not necessarily be worse [24, 36].

Esophagectomy alone

Esophagectomy is preferred over endoscopic resection in the definitive management of higher-risk Tis and T1a disease, as well as deeper pT1b lesions (staged after endoscopic resection). It is also recommended for low-risk cT1b and cT2 tumors (<2cm, G1, and N0) [33].

Traditionally, the esophagectomy was either transhiatal (laparotomy and cervical anastomosis) or transthoracic (most commonly laparotomy and right thoracotomy but variations exist), with meta-analyses showing similar outcomes [37, 38]. Minimally invasive approaches have gained traction more recently with promising results [39-41]. Regardless of the chosen procedure, adequate lymph node dissection is imperative for accurate staging and independently prognostic for survival [42]. An effort should be made to remove at least 15 nodes, although optimal number is still debated [33, 42].

Multimodal therapy

Multimodal therapy is recommended for patients with higher-risk cT1b and cT2 lesions (>2cm or G2+) as well as more locoregionally advanced disease. The preferred treatment for resectable disease is typically preoperative two-agent chemoradiotherapy followed by esophagectomy, a sequence with demonstrated survival benefit over surgery alone [43].

Patients who are not surgical candidates, including those with cervical esophageal cancer or T4b disease invading the trachea, great vessels, or heart, can be managed with definitive chemoradiotherapy. Two prospective randomized trials suggest that definitive chemoradiotherapy achieve comparable outcomes to preoperative chemoradiotherapy followed by esophagectomy in ESCC, making it tempting to pursue this less morbid treatment for all patients [44, 45]. However, these trials have come under criticism and subsequent retrospective studies found a survival benefit with the addition of surgery [46]. Until further evidence is available, preoperative chemoradiotherapy with esophagectomy remains the standard of care for surgical candidates [33].

There is evidence supporting the use of preoperative or perioperative chemotherapy over surgery alone in EAC, but comparisons to preoperative chemoradiotherapy have been underpowered [47-50]. In particular, the perioperative FLOT regimen, established for gastric cancer and EAC of the EGJ, has gained traction recently. These strategies are reasonable alternatives in the management of select patients with distal EAC [33].

Nutrition consultation and placement of a feeding tube should be considered in patients undergoing aggressive multimodality treatment.



Metastatic Disease

Chemotherapy and targeted therapies can help manage symptoms and modestly prolong survival. While systemic therapy is associated with higher toxicity, it does not appear to outweigh symptomatic relief as overall quality of life is not diminished [51]. Extrapolating from reports on gastric cancer, the addition of more chemotherapeutic agents can further extend survival and improve response rate, albeit with greater toxicity [52]. Two-agent chemotherapy is considered first line for most patients with esophageal cancer but three-agent chemotherapy may be appropriate in select medically fit patients with good performance status. The combination of a fluoropyrimidine (e.g., 5-fluorouracil or capecitabine) and a platinum agent (e.g., cisplatin or oxaliplatin) is currently considered first line [33].

The addition of targeted therapies to chemotherapy has produced encouraging results in select patient populations [53-55]. Health Canada and the FDA have approved trastuzumab and ramucirumab for HER2-overexpressing and chemotherapy-refractory patients with GEJ adenocarcinoma, respectively. Other targeted therapies are also showing promising early results, including pembrolizumab which received early FDA approval for select MSI-H/dMMR EGJ adenocarcinoma [33].

There is emerging evidence for aggressive management of oligometastatic esophageal cancer with resection or radiotherapy directed at the primary tumor or oligometastases [56-62]. Among possible oligometastatic sites, lung and liver metastasectomy have the most supporting evidence [59].Ongoing RCTs specifically for oligometastatic esophageal cancer will hopefully shed further light on this subject (RENAISSANCE, NCT03161522) [63]. The management of oligometastatic esophageal cancer is dependent on center of practice. A comprehensive discussion on this subject is beyond the scope of the module; however, relevant features include:

  1. Patient’s age, health, performance status
  2. Number and volume of metastases
  3. Location of metastases (para-aortic nodes, lung, liver are some potential candidates considered more amenable to surgery)
  4. Timeline: metachronous versus synchronous
  5. Basis of diagnosis
  6. Primary tumor status (controlled versus uncontrolled)
  7. T and N stage
  8. Local expertise and resources


Local Palliative Treatment

Dysphagia and esophageal obstruction are the most common complications of esophageal cancer. Obstruction should be considered as a potential cause for persistent nausea and vomiting. A grading scale is useful to communicate the severity of dysphagia [38]:

  • Grade 0: Able to tolerate normal diet without special care.
  • Grade 1: Requires thoroughly-chewed food cut to fragments < 18mm in diameter.
  • Grade 2: Able to swallow only semi-solid food.
  • Grade 3: Liquid diet only.
  • Grade 4: Unable to swallow liquids or saliva.

Numerous options are available for the management of severe dysphagia, including stenting (most commonly used), radiation therapy including EBRT and brachytherapy (also commonly used), endoscopic dilation, chemotherapy, and photodynamic therapy. Multimodal treatment is also reasonable [38]. Palliative esophagectomy is generally discouraged due to high morbidity and mortality, especially in view of the poor prognosis of these patients [79].

Treatment Morbidity

Surgical morbidity

Esophagectomy is a technically challenging surgery associated with considerable morbidity. While mortality rates have declined to less than 10% owing to advances in surgical technique and perioperative management, medical and surgical complications of esophagectomy occur in up to 75% of patients. Important surgical complications include anastomotic leaks, conduit necrosis, esophageal stricture, recurrent laryngeal nerve paralysis, chylothorax, and cardiopulmonary injury [23]. Postoperatively, patients are also at elevated risk for pneumonia, respiratory distress, reflux, delayed gastric emptying, and dumping syndrome even when the stomach is preserved [65]. It is unclear if complication rates improve or worsen with preoperative radiotherapy or chemotherapy [23].

Radiation toxicity

Side effects of esophageal radiation are common and frequently necessitate treatment changes or discontinuation. Concurrent chemotherapy appears to compound toxicity. Among patients treated with radiotherapy in the RTOG 85-01 trial, 25% and 3% experienced acute grade 3 and 4 toxicity, respectively. When chemotherapy was given concurrently, 44% experienced acute grade 3 toxicity and 20% experienced acute grade 4 toxicity. Up to 3% of patients succumbed to chemoradiation-related complications [23]. IMRT has the potential to reduce doses delivered to critical surrounding structures, and a recent meta-analysis suggests that there may be a survival benefit as well[23, 66]. Proton therapy can further reduce radiation to healthy tissue by eliminating the exit dose, though clinical outcomes have not been studied extensively [33]. Some common and serious complications are below.

Acute toxicities
  1. Esophagitis, occuring in >75% [23]
  2. Dysphagia, occuring in >75% [23]
  3. Nausea +/- vomiting (ondansetron, second line steroids)
  4. Anorexia and malnutrition (nutritional support, enteral feeding as needed)
  5. Dehydration
  6. Fatigue
  7. Cough
  8. Dermatitis
  9. Changes in gastric motility 
  10. Prolonged gastric emptying
  11. Myelosuppression with chemoradiation (follow CBC weekly or more frequently as indicated)
  12. Perforated esophagus

These complications typically resolve within 1-2 weeks of completing therapy but often demand close following and aggressive management. 

Subacute and Late toxicities
  1. Esophageal stricture, occuring in >15-20% (dilation is effective) [23] 
  2. Dysphagia
  3. Laryngeal edema
  4. Liver toxicity
  5. Renal toxicity
  6. Cardiac toxicity
  7. Pulmonary toxicity (radiation pneumonitis, pulmonary fibrosis)

Clinically significant end organ damage is uncommon [23].

Prognosis

Overall survival

SEER [22] reports that the 5-year survival rates for esophageal cancer (based on patients diagnosed between 2009 and 2015) are 47% for localized disease, 25% for regional disease, and 5% for distant metastatic disease. 

Factors that independently affect prognosis aside from TNM stage include surgical margins (R-status), age, histologic subtype, and tumor size. Low performance status, weight loss, deep tumor ulceration, sinus tract formation, and fistula formation were associated with poor prognosis. Tumor site and grade have not consistently been shown to affect outcomes independently [33].

Recurrence risk

Approximately 38% of patients treated surgically with curative intent experienced recurrence with a median follow-up time of 46 months. The risk of recurrence is projected to surpass 50% by the sixth year. A majority of recurrences occur in the first two years, with recurrence rate tapering from 27/100 in the first year to 4/100 by the sixth year. The failure pattern is predominantly distant -- 72% of those experiencing recurrence have metastases [67].

Follow up

Patients who have received definitive treatment should be followed closely during the early years, at which time the likelihood of recurrence is highest. This includes history and physical examination, in addition to endoscopic surveillance for those who do not undergo an esophagectomy. Particular emphasis should be placed on nutrition. Further investigations should generally be performed based on clinical presentation.

The value of surveillance imaging and following tumor markers is not known. In particular, CT chest and abdomen appears to be effective in detecting recurrences early, although the implications on survival are unclear [67]. These can be incorporated into the surveillance schedule at the clinician’s discretion.

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